New carbacycline, process for their production and their use as a drug

ABSTRACT

The invention also relates to carbacyclin derivatives of general formula I&#39; ##STR1## wherein R 9  is an alkyl group of 1-10 carbon atoms or the group --C═C--(CH 2 ) m  --R 6  wherein 
     m is 1 to 16 and 
     R 6  is hydroxy on amino.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No. 864,345,filed on May 12, 1986 now abandoned, which is derived from InternationalApplication No. PCT/DE85/00246, filed on July 18, 1985, and also is acontinuation application of U.S. Ser. No. 089,364, filed on Aug. 31,1987 now abandoned, which is derived from International Application No.PCT/DE86/00484 which was filed on Nov. 28, 1986. The entire disclosuresof the two parent applications are hereby incorporated by reference.

The following is the specification of U.S. Ser. No. 089,364, filed onAug. 31, 1987 now abandoned.

The invention relates to new carbacyclin derivatives, process for theirproduction and their use as a drug. In U.S. Pat. No. 4,420,632,9-alkylated carbacyclin derivatives are described which haveantithrombotic, antisecretory and bronchodilating qualities. Inaddition, they act to inhibit platelet aggregations. It was found thatcarbacyclin analogues, chain lengthened in the 9 position, with areactive group in omega-position can be bonded to polymer carriers withonly a small loss of biological activity. The compounds according to theinvention are suitable for the inhibition of platelet aggregations,blood pressure reduction by vasodilation, inhibition of stomach acidsecretion and for the preparation of antibodies to carbacyclins afterchemical bonding with proteins.

The invention relates to carbacyclin derivatives with general formula I:##STR2## in which

Y₁ stands for the radical --CH₂ --X--(CH₂)_(n) --R₁ or the radical##STR3## n, 1 or 3,

R₁, the radical ##STR4## the radical ##STR5## --COCH₃, COOR₂, and R₂ canstand for hydrogen or optionally alkyl with 1-10 C atoms substitutedwith halogen, phenyl, C₁ -C₄ alkoxy or C₁ -C₄ dialkyl amino; cycloalkyl,aryl or a heterocyclic radical, or the radical CONHR₃, with R₃ standingfor hydrogen or an alkanoyl or alkane sulfonyl radical each with 1-10 Catoms,

R₉ stands for the radical --(CH₂)_(m) --R₆ or the radical --(CH₂)_(m-o)--[Z₁ --(CH₂)_(m-p) ]_(x) --[Z₂ --(CH₂)_(m-q) ]_(y) --R₆,

m=2-20,

o, p, and q are less than or equal to 19,

x, y=0, 1 or 2,

Z₁ stands for a cis--CH═CH group, a trans--CH═CH group or a --C═C group,and each of these groups must be separated at least by a methylene groupfrom the C-9 carbon atom of the carbacyclin bicyclic compound,

Z₂ stands for oxygen, sulfur, an NH or an N methyl group,

R₆ stands for amino, methylamino, hydroxy, carboxy or mercapto,

X an oxygen atom or a methylene group,

Y₂ hydrogen or fluorine,

A a --CH₂ --CH₂, trans--CH═CH or --C═C group,

W a free or functionally modified hydroxy methylene group or a free orfunctionally modified ##STR6## and the OH group can be in alpha or betaposition,

D stands for the group ##STR7## a straight-chain, saturated alkylenegroup with 1-5 C atoms, a branched, saturated or a straight-chain orbranched unsaturated alkylene group with 2-5 C atoms, which optionallycan be substituted with fluorine atoms,

o is 1, 2, or 3,

E stands for a direct bond, a --C═C group or a --CH═CR₇ group and R₇stands for a hydrogen atom, an alkyl group with 1-5 C atoms or halogen,

R₄ stands for an alkyl group with 1-10 C atoms, a cycloalkyl group with3-10 C atoms or an aryl group optionally substituted with 6-10 C atoms,or a heterocyclic group,

R₅ stands for a free or functionally modified hydroxy group and, if R₂represents a hydrogen atom, whose salts have physiologicallywell-tolerated bases.

As alkyl groups R₂, straight- or branched-chain alkyl groups with 1-10 Catoms are suitable, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl,decyl.

The alkyl groups R₂ can optionally be substituted once or several timeswith halogen atoms, C₁ -C₄ alkoxy groups, phenyl and di-C₁ -C₄alkylamines. Easily substituted alkyl groups are preferred.

As substituents there can be mentioned, for example, fluorine, chlorineor bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy.

As preferred alkyl groups R₂, there can be mentioned those with 1-4 Catoms, such as methyl, ethyl, propyl, dimethylaminopropyl, isobutyl,butyl.

As aryl groups R₂, both substituted and unsubstituted aryl groups aresuitable, such as phenyl, 1-naphtyl and 2-naphtyl, which can each besubstituted with 1-3 halogen atoms, a phenyl group, 1-3 alkyl groupseach with 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl,carboxyl, hydroxy or alkoxy group with 1-4 C atoms.

Preferred are substituents in the 3 and 4 position on the phenyl ring,for example with fluorine, chlorine, alkoxy or trifluoromethyl or withhydroxy in the 4 position.

The cycloalkyl group R₂ can contain 4-10 preferably 5 and 6 carbon atomsin the ring. The rings can be substituted with alkyl groups with 1-4carbon atoms. For example, there can be cited are cyclopentyl,cyclohexyl, methylcyclohexyl and adamantyl.

Suitable heterocyclic groups R₂ can be 5- and 6-membered heterocyclescontaining at least one hetero atom, preferably nitrogen, oxygen orsulfur. Examples are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and others.

Suitable as the acid residue R₃ are physiologically compatible acidresidues. Preferred acids are organic carboxylic acids and sulfonicacids of 1-5 carbon atoms pertaining to the aliphatic, cycloaliphatic,aromatic, aromatic-aliphatic, and heterocyclic series. These acids canbe saturated, unsaturated and/or polybasic and/or substituted in theusual way. Examples for the substituents are C₁ -C₄ -alkyl, hydroxy, C₁-C₄ -alkoxy, oxo or amino groups, or halogen atoms (F, Cl, Br).

The following carboxylic acids are cited as examples: formic acid,acetic acid, propionic acid, butyric acid, isobutyric acid, valericacid, isovaleric acid, caproic acid, enanthic acid, caprylic acid,pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylicacid, myristic acid, pentadecylic acid, trimethylacetic acid,diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid,cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylicacid, cyclohexanecarboxylic phenylacetic acid, phenoxyacetic acid,methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroaceticacid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid,morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoicacid, benzoic acids substituted by halogen, trifluoromethyl, hydroxy,alkoxy or carboxy groups, nicotinic acid, isonicotinic acid,furan-2-carboxylic acid, cyclopentylpropionic acid. Especially preferredacyl residues are considered to be those of up to 10 carbon atoms.Examples for sulfonic acids are methanesulfonic acid, ethanesulfonicacid, isopropanesulfonic acid, β-chloroethanesulfonic acid,butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid,p-chlorobenzenesulfonic acid, N,N,-dimethylaminosulfonic acid,N,N,-diethylaminosulfonic acid,N,N,-bis-(beta-chloroethyl)-aminosulfonic acid,N,N,-diisobutylaminosulfonic acid, N,N,-dibutylaminosulfonic acid,pyrrolidino-, piperidino-, piperazino-, N-methylpiperazino- andmorpholine-sulfonic acid are suitable, and sulfonic acids with up to 4 Catoms are especially preferred.

The hydroxy groups R₅ and in W can be functionally modified, for exampleby etherification or esterification, and the free or modified hydroxygroups in W can be in the alpha or beta position, free hydroxy groupsbeing preferred.

As ether and acyl radicals, the radicals known to a man of the art aresuitable. Preferred are easily cleavable ether radicals such as thetetrahydropyranyl, tetrahydrofuranyl, alpha-ethoxyethyl, trimethylsilyl,dimethyl-tert-butyl-silyl and tri-p-benzyl-silyl radical. As acylradicals, the same as mentioned for R₃ are suitable; for example therecan be mentioned acetyl, propionyl, butyryl, benzoyl.

As alkyl groups R₄, straight and branched-chain, saturated andunsaturated alkyl radicals, preferably saturated and with 1-10,especially 1-4 C atoms, are suitable.

For example there can be mentioned methyl, ethyl, propyl, butyl,isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl,propenyl, pentenyl, hexenyl.

The cycloalkyl group R₄ can contain 3-10, preferably 5 and 6 carbonatoms in the ring. The rings can be substituted with alkyl groups with1-4 carbon atoms. For example, there can be mentioned cyclopentyl,cyclohexyl, methylcyclohexyl and adamantyl.

As substituted or unsubstituted aryl groups R₄ the following aresuitable, for example: phenyl, 1-naphtyl and 2-naphthyl, which can eachbe substituted with 1-3 halogen atoms, a phenyl group, 1-3 alkyl groupseach with 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl,carboxyl, C₁ -C₄ alkoxy or hydroxy group. Substitution in the 3 and 4position on the phenyl ring is preferred, for example with fluorine,chlorine, C₁ -C₄ alkoxy or trifluoromethyl or in the 4 position withhydroxy.

As heterocyclic groups R₄, 5- and 6-member heterocyclic compounds whichcontain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur,are suitable. For example, there can be mentioned 2-furyl, 2-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 3-furyl, 3-thienyl, among others.

As alkylene group D, straight-chain or branched-chain, saturated andunsaturated alkylene radicals, preferably saturated with up to 5 Catoms, are suitable, which can optionally be substituted with fluorineatoms, 1,2 methylene, 1,1-trimethylene, 1,1-tetramethylene or1,1-pentamethylene. Examples are: methylene, fluoromethylene, ethylene,1,2 propylene, ethylethylene, trimethylene, tetramethylene,pentamethylene, 1-methyltetramethylene, 1-methyl trimethylene,1,1-trimethylene ethylene, 1,1-tetramethylene ethylene.

Especially preferred compounds of this invention are those with E as--C═C-- or --CH═CR₇, where R₇ represents an alkyl group with 1-5 Catoms.

As the alkyl group R₇ with 1-5 C atoms, the groups just named for thealkyl group R₄ are suitable.

With R₇ as halogen, fluorine, chlorine and bromine are meant.

For R₉ as --(CH₂)_(m) --R₆, alkylene groups with 2 to 20 C atoms aresuitable, which can still contain one or more groups Z₁ or Z₂ such as--(CH₂)_(m-o) --[Z₁ --(CH₂)_(m-p) ]_(x) --[Z₂ --CH₂)m-q]_(y) --R₆, wherem=2-20 and o, p, and q together are -16, such as, --(CH₂)₅ --NH₂,--(CH₂)₆ --NHCH₃, --(CH₂)₂ --O--(CH₂)₂ --COOH, --(CH₂)₂ --O--(CH₂)₃--NH₂, --(CH₂)₃ --O--(CH₂)₃ --NH₂, --(CH₂)₂ --O--(CH₂)₂ --O--(CH₂)₂--OH, --(CH₂)₃ ##STR8## (CH₂)₃ --NH₂, --CH₂ --C.tbd.C--(CH₂)₂ --NH₂,--(CH₂)₂ --C═C--(CH₂)₂ --NH₂, --(CH₂)₂ --C═C--(CH₂)₂ --O--(CH₂)₂ --SH,etc.

For salt formation with the free acids (R₂ =H), inorganic and organicbases are suitable, such as they are known to a man of the art for theformation of physiologically well tolerated salts. For example, therecan be mentioned alkali hydroxides such as sodium and potassiumhydroxide, alkaline-earth hydroxides such as calcium hydroxide, ammonia,amines such as ethanolamine, diethanolamine, triethanolamine,N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.

The invention relates further to processes for the production ofcarbacyclins of general formula I according to the invention,characterized in that (a) a compound of general formula IV ##STR9## inwhich A, W, D, E, R₄, R₅ and R₉ have the meanings already given, andwith a Wittig reagent of general formula V and VI or a dianion of theformula VII ##STR10## in which

R₂ has the meaning already given and R₈ stands for the radicals --CH₂--CH₂ --X--(CH₂)_(n) --R₁ or ##STR11## with the meanings alreadymentioned for X, n and R₁ and R₁₁ stand for bromine or chlorine, isreacted in the presence of K-tert-butylate or

(b) a compound of general formula VIII, which is obtained from thecorresponding 4-ester by DIBAH reduction ##STR12## in which A, W, D, E,R₄, R₅, R₉, and Y₂ have the meanings already given, optionally afterprotection of present free hydroxy or amino groups with a haloalkaneacid derivative of general formula IX ##STR13## in which n is 1 or 3,Hal is a chlorine or bromine atom and R₈ is an alkyl radical with 1-4 Catoms or an alkaline metal, is etherified in the presence of a base and,optionally, isomers are then separated in any order and/or protectedhydroxy groups are released and/or free hydroxy groups esterified,etherified and/or a free carboxyl group esterified and/or an esterifiedcarboxyl group saponified or a carboxyl group converted into an amide orwith a physiologically well tolerated base into a salt.

The reaction of the compound of general formula VIII with a haloalkaneacid derivative of general formula IX is performed at temperatures of0°C. to 100° C., preferably 10° to 80° C., in an aprotic solvent orsolvent mixture, for example dimethyl sulfoxide, dimethylformamide,tetrahydrofuran, etc. As bases, the bases known to a man of the art foretherifications are suitable, such as sodium hydride, potassiumtert-butylate, butyllithium, etc.

The starting compounds of formula IV are obtained by the reaction ofcompounds of formula II ##STR14## with Grignard reagents of formula III

R₁₀ --[(CH₂)_(m-q) --Z₂ ]_(y) --[(CH₂)_(m-p) --Z₁ ]_(x) --(CH₂)_(m-o)--Mg--halogen (III),

in which R₄, R₅, A, W, D, E, Z₁, Z₂, m, o, p, q have the indicatedmeanings, in the presence of copper(II) salts and by subsequentintroduction of the upper side chain by Wittig reaction of the 5-ringcarbonyl group and conversion of the group R₁₀ into the group R₆. Forthe group R₁₀, amino groups protected by, for example,1,1,4,4-tetramethyl-1,4-dichlorodisilylethane or by phthalic anhydrideor by other typical amino groups protected by amino protection groups,and by hydroxy groups protected by tert-butyldiphenylsilyl or THP groupsand by conversion into orthoesters or oxazoline-protected carboxylgroups.

After cleavage of the protection groups from nitrogen or after chemicalconversion of the hydroxy or amide groups into amino groups, the desiredsubstituents R₆ ═NH₂ are obtained. For this conversion of a hydroxygroup into an amino group, the Mitsunobu reaction (see Synthesis 1,1981) or the reduction of the azide to amine can be used.

The saponification of the carbacyclin ester is performed according tomethods known to a man of the art, for example with basic catalysts.

The introduction of the ester group COOR₂ for R₁, in which R₂ representsan alkyl group with 1-10 C atoms, occurs according to methods known to aman of the art. The carboxyl compounds are reacted, for example, withdiazohydrocarbons in a way known in the art. Esterification withdiazohydrocarbons occurs, for example, by mixing a solution ofdiazohydrocarbon in an inert solvent, preferably in diethyl ether withthe carboxyl compound in the same or in another inert solvent, forexample, methylene chloride. After the reaction is finished in 1 to 30minutes, the solvent is removed and the ester is purified in the usualway. Diazoalkanes are either known or can be produced by known methods(Org. Reactions Vol. 8, pages 389-394 (1954)).

The introduction of the ester group COOR₂ for R₁, in which R₂ representsa substituted or unsubstituted aryl group, occurs according to methodsknown to a man of the art. For example, the carboxyl compounds arereacted with the corresponding aryl hydroxy compounds withdicyclohexylcarbodiimide in the presence of a suitable base, for examplepyridine or triethylamine, in an inert solvent. As a solvent, methylenechloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran,preferably chloroform, are suitable. The reaction is performed attemperatures between -30° C. and +50° C., preferably at +10° C.

The carbacyclin derivatives of general formula I with R₁ representing acarboxyl group can be converted, with suitable amounts of thecorresponding inorganic base, with neutralization, into salts. Forexample, by dissolving the corresponding PG acids in water whichcontains the stoichiometric amount of the base, the solid inorganic saltif obtained after evaporation of the water or after addition of awater-miscible solvent, for example, alcohol or acetone.

Production of the amine salts occurs in the usual way. In addition, thePG acid is dissolved, for example, in a suitable solvent such asethanol, acetone, diethyl ether or benzene and at least thestoichiometric amount of the amine of this solution is added. In doingso the salt usually precipitates in solid form or is isolated in theusual way after evaporation of the solvent.

The functional modification of the free OH group occurs according tomethods known to a man of the art. To introduce the ether protectiongroup the reaction is performed with, for example, dihydropyran inmethylene chloride or chloroform while using an acidic condensing agent,for example p-toluenesulfonic acid. An excess of dihydropyran is used,preferably 4 to 10 times the amount theoretically needed. The reactionis normally finished in 15 to 30 minutes at 0° C.-30° C.

The introduction of the acyl protection groups occurs by reacting acompound of general formula I in a way known in the art with acarboxylic acid derivative, such as acid chloride, acid anhydride, amongothers

The release of a functionally modified OH group to the compounds ofgeneral formula I occurs according to known methods. For example, thecleavage of ether protection groups is performed in an aqueous solutionof an organic acid, such as acetic acid, propionic acid, among others,or in an aqueous solution of an inorganic acid, such as hydrochloricacid. To improve the solubility, an water-miscible inert organic solventis suitably added. Suitable organic solvents are, for example, alcoholssuch as methanol and ethanol, and ethers, such as dimethoxyethane,dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. Thecleavage is preferably performed at temperatures between 20° C. and 80°C.

The cleavage of the silyl ether protection group is performed, forexample, with tetrabutylammonium fluoride. Tetrahydrofuran, diethylether, dioxane, and methylene chloride, for example, are suitable assolvents. The cleavage is performed preferably at temperatures between0° C. and 80° C.

Saponification of the acyl groups is performed, for example, with alkalior alkaline-earth carbonates or hydroxides in an alcohol or the aqueoussolution of an alcohol. As alcohols, aliphatic alcohols are suitable,such as methanol, ethanol, butanol, etc., preferably methanol. As alkalicarbonates and hydroxides there can be mentioned potassium and sodiumsalts, but the potassium salts are preferred. As alkaline-earthcarbonates and hydroxides, calcium carbonate, calcium hydroxide andbarium carbonate are, for example, suitable. The reaction takes place at-10° C. to 70° C., preferably at 25° C.

The introduction of the amide group CONHR₃ for R₁ occurs according tomethods known to a man of the art. Carboxylic acids of general formula I(R₂ =H) are first converted, in the presence of a tertiary amine such astriethylamine, with chloroformic acid isobutyl ester, into the mixedanhydride. The reaction of the mixed anhydride with the alkali salt ofthe corresponding amide or with ammonia (R₃ ═H) occurs in an inertsolvent or solvent mixture, such as tetrahydrofuran, dimethoxyethane,dimethylformamide, and hexamethylphosphoric acid triamide attemperatures between -30° C. and +60° C., preferably at 0° C. to 30° C.

A further possibility for the introduction of the amide group CONHR₃ forR₁ consists in reacting a 1-carboxylic acid of general formula I (R₂═H), in which free hydroxy groups are protected intermediately, withcompounds of general formula X

    O═C═N--R.sub.3                                     (X),

in which R₃ has the above-mentioned meaning.

The reaction of the compound of general formula I (R₁ ═COOH) with anisocyanate of general formula VIII occurs optionally with the additionof a tertiary amine, such as triethylamine or pyridine. The reaction canoccur without solvent or in an inert solvent, preferably acetonitrile,tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethylether, toluene, at temperatures between -80° C. to 100° C., preferablyat 0° C. to 30° C.

If the starting product contains OH groups in the prostane radical,these OH groups are also reacted. If, ultimately, end productscontaining free hydroxy groups in the prostane radical are desired,suitably a starting product is used in which these free hydroxy groupsare intermediately protected by preferably easily cleavable ether oracyl radicals.

All remaining compounds of formula I can be produced according toprocesses described in laid-open specifications DE-OS Nos. 28 45 770,3237 200, 33 22 893 and 34 05 181.

The carbacyclins of formula I, in which R₉ stands for the radical--(CH₂)_(m) --R₆ or --(CH₂)_(m-o) --[Z₁ --(CH₂)_(m-p) ]_(x) --[Z₂--CH₂)m-q]y---₆ with R₆ as NH₂, NHCH₃, OH, COOH, or SH group, can bebonded very well without great loss of biological activity to polymercarriers. The new carbacyclins prevent the formation of plateletaggregations on the surface of these polymer carriers, such as vascularprosthetic devices or artificial heart valves. After chemical bonding toproteins, the compounds of formula I are suitable for the preparation ofantibodies to prostacyclins of general formula I.

The compounds of this invention are furthermore suitable for therapy ofdiseases of the cardiovascular system, the stomach, the pancreas, theliver and the kidneys. They cause blood pressure reduction andbronchodilation. They are additionally suitable for the inhibition ofplatelet aggregation. Consequently, the new carbacyclin derivatives offormula I represent valuable pharmaceutical active ingredients.Furthermore, compared with corresponding prostaglandins andprostacyclins, they exhibit higher specificity and above all asubstantially longer effectiveness in the same activity spectrumCompared to PGI₂, they are distinguished by higher stability. The hightissue specificity of the new carbacyclins is shown with the study ofsmooth muscle organs, such as the guinea pig ileum or the isolatedrabbit trachea, where a considerably lesser stimulation can be observedthan with the application of natural prostaglandins of the E, A or Ftype.

The new carbacyclin analogues possess qualities typical forprostacyclins, such as reduction of the peripheral arterial and coronaryvascular resistance, inhibition of platelet aggregation and dissolutionof platelet clots, myocardial cytoprotection, reduction of the systemicblood pressure without at the same time reducing cardiac output andcoronary blood circulation; treatment of stroke, prevention and therapyfor coronary heart diseases, coronary thrombosis, cardiac infarction,peripheral arterial diseases, arteriosclerosis and thrombosis,prevention and therapy of ischemic attacks of the central nervoussystem, shock therapy, inhibition of bronchoconstriction, inhibition ofstomach acid secretion and cytoprotection of the stomach and intestinalmucous membrane; cytoprotection in the liver, pancreas and kidneys,antiallergic qualities, reduction of pulmonary vascular resistance andpulmonary blood pressure, stimulation of kidney blood circulation, useinstead of heparin or as an adjunct in dialysis or blood filtration,storage of blood plasma supplies, especially of blood platelet supplies,inhibition of labor pains, treatment of pregnancy toxicosis, elevationof cerebral blood circulation, treatment of asthma, etc. In addition,the new carbacyclin analogues possess antiproliferative qualities. Thenew carbacyclins can also be used in combination, for example, with betablockers or diuretics.

The new carbacyclins are furthermore distinguished by the suppression ofrejection reactions and by its antimetastatic effect. With them,Botallo's duct (before operations) is kept open. They are furthersuitable for diarrhea treatment and to improve bowel movement.

The dose of the compounds is 1-1500 micrograms/kg/day, if they areadministered to human patients. The unit dose for the pharmaceuticallyacceptable vehicles is 0.01-100 mg.

With intravenous injection in awake, hypertonic rats in doses of 5, 20and 100 micrograms/kg body weight, the compounds according to theinvention exhibit stronger blood pressure reduction and longer lastingeffects than PGE₂ and PGA₂ without causing, as with PGE₂, diarrhea, oras with PGA₂, cardiac arrhythmias.

With intravenous injection in anesthetized rabbits, the compoundsaccording to the invention exhibit, compared to PGE₂ and PGA₂, strongerand considerably longer lasting blood pressure reduction, withoutinfluencing other smooth muscle organs or organ functions.

For parenteral administration, sterile, injectable, aqueous or oilysolutions are used. For oral application, tablets, dragees or capsulesare suitable, for example.

The invention thus relates also to drugs based on compounds of generalformula I and usual auxiliary agents and carriers.

The active ingredients according to the invention should function inconjunction with the usual auxiliary agents known in galenicals, such asfor the production of blood pressure reduction agents.

The unit dose range for the ampoule is 0.1-0.5 mg, for tablets 0.1-1 mg.

EXAMPLE 15-(E)-{7-hydroxy-6-9-[(E)-3-hydroxy-4-methyl-oct-1-en-6-inyl]-[6-amino-hexyl]-bicyclo[3.3.0]octan-3-yliden}pentaicacid

221 mg (0.5 mmol) of7alpha-tetrahydropyran-2-yl-oxy)-6beta-[(E)-4-methyl-3-(tetrahydropyran-2-yl-oxy)-oct-1-en-6-inyl]-bicyclo-[3.3.0]-oct-1-en-3-oneand 12 mg of Cu(OAc)₂.H₂ O in 6 ml of absolute tetrahydroduran weremixed slowly at -15° C. with a Grignard reagent, prepared from 670 mg (2mmol) of 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane-1-hexylbromide and 103 mg of magnesium chips in 2 ml of absolute ether, until apitch black color was achieved after several color changes.

After working up with NH₄ Cl, the raw product was subsequently silylatedaccording to the following formula for the starting material and the rawproduct, which according to TLC still contained 13% of the startingmaterial, was subjected to a Wittig reaction with 10 equivalent of (4carboxybutyl)triphenylphosphonium bromide/potassium tert-butylate indimethyl sulfoxide-tetrahydrofuran=2:1. After 3 hours of stirring at 30°C., it was mixed with ice water, carefully neutralized with citric acidand extracted with ether. After chromatography on silica gel, pure5-E-isomer was obtained, which yielded the desired 5-E end product aftercleavage of the protection group with AcOH-H₂ O-THF.

IR (oil film) 3400-3000 cm⁻¹ (NH₂ and OH) 1710-1600 cm⁻¹ (acid carbonyland carboxylate)

2,2,5,5-tetramethyl-aza-2,5-disilacyclopentane-1-hexyl bromide wasprepared as follows:

10 g (38.3 mmol) of 6-bromine-1-hexylamine hydrobromide and 8.25 g (38.3mmol) of 1,2-bis(chlorodimethylsilyl)ethane were stirred in the presenceof 15.9 ml (15 mmol) of triethylamine in 115 ml of methylene chloridefor 3 hours at 24°, and triethylamine hydrochloride precipitated. Aftersuctioning of the triethylamine hydrochloride and rewashing withmethylene chloride, evaporation took place and the residue was absorbedin 50 ml of dry hexane, while the remaining triethylamine hydrochlorideprecipitated and was filtered off. After evaporation, about 11.52 g(93.3%) was obtained, which was distilled at 92°-102°/0.05 mm. Thedistillate is, like the raw product, slightly cloudy.

EXAMPLE 25-(E)-{7-(tetrahydropyran-2-yl-oxy)-6-(E)-4-methyl-3-(tetrahydropyran-2-yl-oxy)-oct-1-en-6-inyl]-9-[5-hydroxy-pentyl]-bicyclo-[3.3.0]-octan-3-yliden}-pentaic acid

To 740 mg (1.67 mmol) of 7 alpha-tetrahydropyran-2-yl-oxy)-6beta-[(E)-4-methyl-3-(tetrahydropyran-2-yl-oxy)-oct-1-en-6-inyl]bicyclo[3.3.0]oct-1-en-3-oneand 40.2 mg of Cu(OAc)₂ . H₂ O in 20 ml of absolute tetrahydrofuran wasinstilled in 10 minutes at -15°, a Grignard solution produced from 3.949g of 5-tert-butyldimethylsilyloxypentylbromide and 689 mg of magnesiumchips in 15 ml of absolute ether until a pitch black color occurred.After working up, the raw product was chromatographed on a column ofabout 150 g of SiO₂ in hexane-ether and 932 mg=86.4% pure bicyclicketone was obtained. This 932 mg (1.445 mmol) was reacted analogously toExample 1 with excess (4-carboxybutyl)triphenylphosphonium bromide andafter working up the isomeric compounds were separated by chromatographyin hexane-ether on 150 g of fine silica gel, and pure (e)-stereoisomerwas obtained. By treatment with a tetrabutylammonium fluoride solutionin THF, the tert-butyldimethylsilyl protection group saponified on theC-9 of the bicyclooctane skeleton selectively and the title compoundformed. The reaction with acetic acid-H₂ O-THF/80° then leads to thefree carbacyclin derivative 5(E){7-hydroxy-6[(E)-4-methyl-3-hydroxyoct-1-en-6-inyl]-9[5-hydroxyl-pentyl]-bicyclo[3.3.0]-octan-3-yliden}-pentaic acid.

IR (oil film) 3300-3000 cm⁻¹ (OH). 1740-1710 cm⁻¹ (acid carbonyl/wide/).

5-tert-butyldimethylsilyloxy-pentyl bromide was prepared as follows:

10.45 g (50 mmol) of 5-bromovaleric acid ethyl ester was reduced at 0°with 1.043 g of LiAIH₄ in 100 ml of absolute tetrahydrofuran, worked upwith ice water, 2N H₂ SO₄ and chromatographed with pentane, 20% ether ona column with 275 g of silica gel, and 5.88 g of 5-bromopentyl alcoholwas obtained. 7.01 g (42 mmol) of 5-bromopentyl alcohol was stirred in20 ml of DMF with 3.571 g of imidazole and 7.906 g (52.5 mmol) oftert-butyldimethylsilyl chloride for 2 hours at 24°, ice water added andextracted with hexane/ether 1:1, and 12.58 g of raw product wasobtained, which yielded 8.93 g (75%) of the title compound in pentaneafter chromatography on silica gel.

The following is the specification of U.S. Ser. No. 864,345, filed onMay 12, 1986 now abandoned.

The invention relates to novel carbacyclin derivatives, processes fortheir preparation, as well as use thereof as medicinal agents. U.S. Pat.No. 4,420,632 discloses 9-alkylated carbacyclin derivatives exhibitingantithrombotic, antisecretory and bronchodilating properties. Theyfurthermore act as thrombocyte aggregation inhibitors.

It has been found that, by substitution of the methylene group in the3-position of these carbacyclins by oxygen, or by chain extension in the9-position, biologically active derivatives are obtained exhibitinglonger-lasting effectiveness, greater selectivity, and improvedefficacy. The derivatives with lengthening of the chain in the9-position can be bound to polymeric substrates with an only minor lossof biological activity. The compounds of this invention havebronchodilatory effects and are suitable for inhibition of thrombocyteaggregation, for lowering blood pressure via vasodilation, and forinhibition of gastric acid secretion.

The invention relates to carbacyclin derivatives of general Formula I##STR15## wherein

n is 1 or 3

R₁ is the residue ##STR16## the residue ##STR17## the residue COOR₂wherein R₂ can mean hydrogen or alkyl of 1-10 carbon atoms optionallysubstituted by halogen, phenyl, C₁ -C₄ -alkoxy or C₁ -C₄ -dialkylamino;cycloalkyl, aryl, or a heterocyclic residue, or is the residue CONHR₃with R₃ meaning hydrogen or an alkanoyl or alkanesulfonyl residue ofrespectively 1-10 carbon atoms,

R₉ is an alkyl group of 1-10 carbon atoms or the group--C.tbd.C--(CH₂)_(m) --R₆ wherein

m is 1 to 16 and

R₆ is hydrogen, hydroxy, amino or trimethylsilyl,

X is an oxygen atom or, if R₉ means an alkyl group of 5-10 carbon atoms,a methylene group,

Y is hydrogen or fluorine,

A is a --CH₂ --CH₂ --, trans--CH═CH-- or --C.tbd.C-- group,

W is a free or functionally modified hydroxymethylene group or a free orfunctionally modified ##STR18## wherein the OH-group can be in the α- orβ-position,

D is the group ##STR19## a straight-chain, saturated alkylene group of1-5 carbon atoms, a branched saturated or a straight-chain or branchedunsaturated alkylene group of 2-5 carbon atoms which latter can beoptionally substituted by fluorine atoms,

o is 1, 2 or 3,

E is a direct bond, a --C.tbd.C-- group, or a --CH═CR₇ group wherein R₇is a hydrogen atom, an alkyl group of 1-5 carbon atoms, or halogen,

R₄ is an alkyl group of 1-10 carbon atoms, a cycloalkyl group of 3-10carbon atoms, or an optionally substituted aryl group of 6-10 carbonatoms, or a heterocyclic group, and

R₅ is a free or functionally modified hydroxy group, and

if R₂ means a hydrogen atom, the salts thereof with physiologicallycompatible bases.

The compounds of Formula I' represent (5E)- as well as (5Z)-isomers.

Alkyl groups R₂ can be straight- or branched-chain alkyl groups of 1-10carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl,hexyl, decyl.

The alkyl groups R₂ can optionally be mono- to polysubstituted byhalogen atoms, C₁ -C₄ -alkoxy groups, phenyl, and di-C₁ -C₄-alkylamines. Alkyl groups which are monosubstituted are preferred.

Examples for substituents are fluorine, chlorine or bromine atoms,phenyl, dimethylamino, diethylamino, methoxy, ethoxy.

Preferred alkyl groups R₂ are those of 1-4 carbon atoms, such as, forexample, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl.

Suitable aryl groups R₂ are substituted as well as unsubstituted arylgroups, such as, for example, phenyl, 1-naphthyl, and 2-naphthyl, eachof which can be substituted by 1-3 halogen atoms, a phenyl group, 1-3,alkyl groups of respectively 1-4 carbon atoms, a chloromethyl,fluoromethyl, trifluoromethyl, carboxy, hydroxy, or alkoxy group of 1-4carbon atoms.

The substituents in the 3- and 4- positions on the phenyl ring arepreferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl,or in the 4-position by hydroxy.

The cycloalkyl group R₂ can contain in the ring 4-10, preferably 5 and 6carbon atoms. The rings can be substituted by alkyl groups of 1-4 carbonatoms. Examples that can be cited are cyclopentyl, cyclohexyl,methylcyclohexyl and adamantyl.

Suitable heterocyclic groups R₂ can be 5- and 6-membered heterocyclescontaining at least one hetero atom, preferably nitrogen, oxygen orsulfur. Examples are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and others.

Suitable as the acid residue R₃ are physiologically compatible acidresidues. Preferred acids are organic carboxylic acids and sulfonicacids of 1-15 carbon atoms pertaining to the aliphatic, cycloaliphatic,aromatic, aromatic-aliphatic, and heterocyclic series. These acids canbe saturated, unsaturated and/or polybasic and/or substituted in theusual way. Examples for the substituents are C₁ -C₄ -alkyl, hydroxy, C₁-C₄ -alkoxy, oxo or amino groups, or halogen atoms (F, Cl, Br).

The following carboxylic acids are cited as examples: formic acid,acetic acid, propionic acid, butyric acid, isobutyric acid, valericacid, isovaleric acid, caproic acid, enanthic acid, caprylic acid,pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylicacid, myristic acid, pentadecylic acid, trimethylacetic acid,diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid,cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylicacid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid,methoxyacetic acid, ethoxyacetic acid, mono-, di- and tri-chloroaceticacid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid,morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoicacid, benzoic acids substituted by halogen, trifluoromethyl, hydroxy,alkoxy or carboxy groups, nicotinic acid, isonicotinic acid,furan-2-carboxylic acid, cyclopentylpropionic acid. Especially preferredacyl residues are considered to be those of up to 10 carbon atoms.Examples for sulfonic acids are methanesulfonic acid, ethanesulfonicacid, isopropanesulfonic acid, β-chloroethanesulfonic acid,butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid,p-chlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid,N,N-diethylaminosulfonic acid, N,N-bis(β-chloroethyl)aminosulfonic acid,N,N-diisobutylaminosulfonic acid, N,N-dibutylaminosulfonic acid,pyrrolidino-, piperidino-, piperazino-, N-methylpiperazino- andmorpholinosulfonic acid, sulfonic acids of up to 10 carbon atoms beingespecially preferred.

The hydroxy groups R₅ and those in W can be functionally modified, forexample by etherification or esterification, wherein the free ormodified hydroxy groups in W can be in the α- or β-position, freehydroxy groups being preferred.

Suitable as the ether and acyl residues are those known to personsskilled in the art. Ether residues that can be readily split off arepreferred, such as, for example the tetrahydropyranyl,tetrahydrofuranyl, α-ethoxyethyl, trimethylsilyl,dimethyl-tert-butylsilyl and tri-p-benzylsilyl residue. The acylresidues are the same as recited for R₃ ; worth mentioning by name, forexample, are acetyl, propionyl, butyryl, benzoyl.

Suitable as the alkyl group R₄ are straight-and branched-chain,saturated and unsaturated alkyl residues, preferably saturated ones, of1-10, especially 1-4 carbon atoms.

Examples that can be cited are methyl, ethyl, propyl, butyl, isobutyl,tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl,pentenyl, hexenyl, or carboxy-group-substituted benzoic acids, nicotinicacid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionicacid. Especially preferred acyl residues are those of up to 10

The cycloalkyl group R₄ can contain in the ring 3-10, preferably 5 and 6carbon atoms. The rings can be substituted by alkyl groups of 1-4 carbonatoms. Examples are cyclopentyl, cyclohexyl, methylcyclohexyl andadamantyl.

Suitable substituted or unsubstituted aryl groups R₄ are, for example:phenyl, 1-naphthyl and 2-naphthyl, each of which can be substituted by1-3 halogen atoms, a phenyl group, 1-3 alkyl groups of 1-4 carbon atomseach, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, C₁ -C₄-alkoxy or hydroxy group. The substitution in the 3- and 4-positions onthe phenyl ring is preferred, for example by fluorine, chlorine, C₁ -C₄-alkoxy or trifluoromethyl, or in the 4-position by hydroxy.

Suitable heterocyclic groups R₄ are 5- and 6-membered heterocyclescontaining at least one hetero atom, preferably nitrogen, oxygen orsulfur. Examples that can be cited are 2-furyl, 2-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 3-furyl, 3-thienyl, and others.

The alkylene group D can be straight-chain or branched-chain, saturatedand unsaturated alkylene residues, preferably saturated ones of up to 5carbon atoms which can optionally be substituted by fluorine atoms,1,2-methylene, 1,1-trimethylene, 1,1-tetramethylene or1,1-pentamethylene. Examples are: methylene, fluoromethylene, ethylene,1,2-propylene, ethylethylene, trimethylene, tetramethylene,pentamethylene, 1-methyltetramethylene, 1-methyltrimethylene,1,1-trimethylenethylene, 1,1-tetramethylenethylene.

Especially preferred compounds of this invention are those wherein E is--C.tbd.C-- or --CH═CR₇ -- with R₇ meaning an alkyl group of 1-5 carbonatoms.

Suitable alkyl groups R₇ of 1-5 carbon atoms are the groups alreadycited for the alkyl group R₄.

In the meaning of halogen, R₇ is fluorine, chlorine and bromine.

Suitable as the alkyl group R₉ of 1-10 carbon atoms are the groupsrecited above for R₄.

Among the residues --C.tbd.C--(CH₂)_(m) --R₆ for R₉, residues with m=1-8are preferred.

Inorganic and organic bases are suitable for salt formation with thefree acids (R₂ =H), as they are known to persons skilled in the art forthe formation of physiologically compatible salts. Examples are: alkalihydroxides, such as sodium and potassium hydroxide, alkaline earthhydroxides, such as calcium hydroxide, ammonia, amines, such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine,morpholine, tris(hydroxymethyl)methylamine, etc.

The invention relates furthermore to a process for the preparation ofthe carbacyclins of general Formula I according to this inventionwherein X means an oxygen atom, characterized by conventionallyetherifying, in the presence of a base, a compound of general FormulaII' ##STR20## wherein R₄, R₅, R₉, A, W, Y, D and E have the meaningsgiven above,

optionally after blockage of free hydroxy groups present,

with a haloalkanoic acid derivative of general Formula III ##STR21##wherein n is 1 or 3; Hal is a chlorine or bromine atom; and R₈ is analkyl residue of 1-4 carbon atoms or an alkali metal,

and optionally subsequently, in any desired sequence, separating isomersand/or liberating blocked hydroxy groups and/or esterifying, etherifyingfree hydroxy groups and/or esterifying a free carboxy group and/orsaponifying an esterified carboxy group, or converting a carboxy groupinto an amide or, with a physiologically compatible base, into a salt.

Reaction of the compound of general Formula II with a haloalkanoic acidderivative of general Formula III is conducted at temperatures of 0° C.to 100° C., preferably 10°-80° C., in an aprotic solvent or solventmixture, for example dimethyl sulfoxide, dimethylformamide,tetrahydrofuran, etc. Suitable bases are the bases known to one skilledin the art for etherifications, e.g. sodium hydride, potassiumtertbutylate, butyllithium, etc.

Saponification of the carbacyclin esters is performed according to themethods known to persons skilled in the art, such as, for example, withalkaline catalysts.

The ester group COOR₂ wherein R₂ is an alkyl group of 1-10 carbon atomsis introduced for R₁ in accordance with the methods known to one skilledin the art. The carboxy compounds are, for example, conventionallyreacted with diazo hydrocarbons. Esterification with diazo hydrocarbonstakes place, for example, by mixing a solution of the diazo hydrocarbonin an inert solvent, preferably in diethyl ether, with the carboxycompound in the same or in another inert solvent, e.g. methylenechloride. After the reaction is finished within 1-30 minutes, thesolvent is removed and the ester purified as usual. Diazo alkanes areeither known or can be prepared according to known methods [Org.Reactions 8: 389-394 (1954)].

Introduction of the ester group COOR₂ for R₁ wherein R₂ is a substitutedor unsubstituted aryl group takes place by means of methods known tothose skilled in the art. The carboxy compounds are reacted, forexample, with the corresponding aryl hydroxy compounds withdicyclohexylcarbodiimide in the presence of a suitable base, e.g.pyridine or triethylamine, in an inert solvent. Suitable solvents aremethylene chloride, ethylene chloride, chloroform, ethyl acetate,tetrahydrofuran, preferably chloroform. The reaction is conducted attemperatures of between -30° C. and +50° C., preferably at +10° C.

The carbacyclin derivatives of general Formula I wherein R₁ means acarboxy group can be converted into salts with suitable amounts of thecorresponding inorganic bases under neutralization For example, bydissolving the corresponding PG acids in water containing thestoichiometric quantity of the base, the solid inorganic salt isobtained after evaporation of the water or after addition of awater-miscible solvent, e.g. alcohol or acetone.

The amine salts are produced in the usual way. For this purpose, the PGacid is, for example, dissolved in a suitable solvent, such as ethanol,acetone, diethyl ether, or benzene, and at least the stoichiometricamount of the amine is added to this solution. During this process, thesalt is ordinarily obtained in the solid form or is conventionallyisolated after evaporation of the solvent.

Functional modification of the free OH-groups takes place according tothe methods known to persons skilled in the art. For introduction of theether blocking groups, for example, the reaction is executed withdihydropyran in methylene chloride or chloroform with the use of anacidic condensation agent, e.g. p-toluenesulfonic acid. Dihydropyran isadded in excess, preferably in four to ten times the amount requiredtheoretically. The reaction is normally concluded at 0° C. to 30° C.after 15-30 minutes.

The acyl blocking groups are introduced by reacting a compound ofgeneral Formula I in a manner known per se with a carboxylic acidderivative, e.g. an acid chloride, acid anhydride, and others.

Liberation of a functionally modified OH-group to obtain the compoundsof general Formula I takes place according to known methods. Forexample, ether blocking groups are split off in an aqueous solution ofan organic acid, e.g. acetic acid, propionic acid, and others, or in anaqueous solution of an inorganic acid, e.g. hydrochloric acid. Forimproving solubility, a water-miscible, inert organic solvent issuitably added. Organic solvents that can be used are, for example,alcohols, such as methanol and ethanol, and ethers, such asdimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran isutilized with preference. The splitting-off step is preferably performedat temperatures of between 20° C. and 80° C.

The silyl ether blocking groups are split off, for example, withtetrabutylammonium fluoride. Examples of suitable solvents aretetrahydrofuran, diethyl ether, dioxane, methylene chloride, etc. Thesplitting-off step is preferably conducted at temperatures of between 0°C. and 80° C.

Saponification of the acyl groups takes place, for example, with alkalior alkaline earth carbonates or hydroxides in an alcohol or in theaqueous solution of an alcohol. Suitable alcohols are aliphaticalcohols, e.g. methanol, ethanol, butanol, etc., preferably methanol.Alkali carbonates and hydroxides that can be mentioned are potassium andsodium salts, but the potassium salts are preferred. Examples ofsuitable alkaline earth carbonates and hydroxides are calcium carbonate,calcium hydroxide and barium carbonate. The reaction takes place at -10°C. to 70° C., preferably at 25° C.

Introduction of the amide group CONHR₃ for R₁ is performed according tomethods known to those skilled in the art. The carboxylic acids ofgeneral Formula I (R₂ ═H) are first converted into the mixed anhydridewith the isobutyl ester of chloroformic acid in the presence of atertiary amine, e.g. triethylamine. The reaction of the mixed anhydridewith the alkali salt of the corresponding amide or with ammonia (R₃ ═H)is conducted in an inert solvent or solvent mixture, such as, forexample, tetrahydrofuran, dimethoxyethane, dimethylformamide,hexamethylphosphoric triamide, at temperatures of between -30° C. and+60° C., preferably at 0°-30° C.

Another possibility for introducing the amide group CONHR₃ for R₁resides in reacting a 1-carboxylic acid of general Formula I' (R₂ ═H)wherein free hydroxy groups are intermediately protected, with compoundsof general Formula IV'

    O═C═N--R.sub.3                                     IV'

wherein R₃ has the meanings given above.

Reaction of the compound of general Formula I' (R₁ ═COOH) with anisocyanate of general Formula IV' optionally takes place with additionof a tertiary amine, such as, for example, triethylamine or pyridine.The reaction can be performed without solvents or in an inert solvent,preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide,methylene chloride, diethyl ether, toluene, at temperatures of between-80° C. to 100° C., preferably at 0°-30° C.

If the starting compound contains OH-groups in the prostane residue,then these OH-groups are likewise reacted. If, in the final analysis,end products are desired which contain free hydroxy groups in theprostane residue, starting compounds are suitably utilized wherein theseare intermediately blocked by preferably readily cleavable ether or acylresidues.

All the remaining compounds of Formula I' can be prepared according toprocesses described in Laid-Open Applications DOS's Nos. 2,845,770;3,237,200; 3,322,893; and 3,405,181. In case the residue R₉ is analkynyl group, the residue R₉ can be introduced according to the methoddisclosed by R. T. Hansen et al., JACS 100:2244 (1978).

The compounds of this invention are especially suitable for therapy ofdiseases of the cardiovascular system, the stomach, the pancreas, theliver, and the kidney. They have hypotensive and bronchodilatoryeffects. They are furthermore suited for inhibiting thrombocyteaggregation. Consequently, the novel carbacyclin derivatives of FormulaI represent valuable pharmaceutically active agents. Moreover, theyexhibit, with a similar spectrum of activity, a higher specificity and,above all, a substantially longer lasting efficacy as compared withcorresponding prostaglandins and prostacyclins As compared with PGI₂,they are distinguished by higher stability. The high tissue specificityof the novel carbacyclins is demonstrated in a study on smooth muscleorgans, such as, for example, on the guinea pig ileum or on the isolatedrabbit trachea where a substantially lower stimulation can be observedthan in the administration of natural prostaglandins of the E-, A- orF-type.

The novel carbacyclin analogs exhibit the properties typical forprostacyclins, such as, for example, lowering of peripheral arterial andcoronary vascular resistance, inhibition of thrombocyte aggregation anddissolution of platelet thrombi, myocardial cytoprotection, lowering ofsystemic blood pressure without simultaneously lowering stroke volumeand coronary blood flow; treatment for stroke, prophylaxis and therapyof coronary heart disease, coronary thrombosis, cardiac infarction,peripheral arterial diseases, arteriosclerosis and thrombosis,prophylaxis and therapy of ischemic attacks of the CNS system, therapyfor shock, inhibition of bronchoconstriction, inhibition of gastric acidsecretion and cytoprotection of gastric and intestinal mucosa;cytoprotection in liver, pancreas, and kidney, anti-allergic properties,lowering of pulmonary vascular resistance and pulmonary blood pressure,promotion of renal blood flow, utilization in place of heparin or asadjuvant in dialysis or hemofiltration, preservation of stored bloodplasma, especially stored blood platelets, inhibition of labor,treatment of gestational toxicosis, enhancement of cerebral blood flow,treatment of asthma, etc. The novel carbacyclin analogs furthermoreexhibit antiproliferative properties. The novel carbacyclins canadditionally be utilized in combination, for example, with β-blockers ordiuretics.

The novel carbacyclins are furthermore also distinguished by suppressingrejection reactions and by their antimetastatic activity. They act tokeep Botallo's duct open (before surgery). They are furthermore suitablefor treatment of diarrhea and for improving bowel action.

The carbacyclins of Formula I wherein R₉ is the residue --C≳C--(CH₂)_(m)--R₆ wherein R₆ is an OH-- or NH₂ -- up can be bound very readily andwithout appreciable loss of biological activity to polymeric substrates.The novel carbacyclins prevent formation of thrombocyte aggregates onthe surface of these polymeric substrates, such as, for example,artificial blood vessels or artificial heart valves.

Dosage of the compounds is 1-1,500 μg/kg/day if administered to humanpatients. The unit dosage for the pharmaceutically acceptable carrier is0.01-100 mg.

With intravenous injection administered to nonanesthetized, hypertonicrats in doses of 5, 20, and 100 μg/kg body weight, the compounds of thisinvention exhibit a stronger hypotensive effect and a more prolongedduration of efficacy than PGE₂ and PGA₂ without triggering diarrhea, asdoes PGE₂, or cardiac arrhythmias, as does PGA₂.

Upon intravenous injection administered to anesthetized rabbits, thecompounds of this invention show, as compared with PGE₂ and PGA₂, astronger and also considerably prolonged hypotensive activity withoutaffecting other smooth muscle organs or organ functions. Sterile,injectable, aqueous or oily solutions are used for parenteraladministration. Suitable for oral administration are, for example,tablets, dragees or capsules.

The invention accordingly also concerns medicinal agents based on thecompounds of general Formula I' and conventional auxiliary agents andexcipients.

The active agents of this invention are to serve, in conjunction withthe auxiliary ingredients known and customary in galenic pharmacy, forexample for the preparation of hypotensors.

The unit dosage range for an ampoule is 0.1-0.5 mg, for tablets 0.1-1mg.

EXAMPLE 31β-Methyl-7α-(tetrahydropyran-2-yloxy)-6β-[3α-(tetrahydropyran-2-yloxy)-4-methyl-6,7-tetradehydrotrans-1-octenyl]bicyclo[3.3.0]-octan-3-one

At -5°, 27 ml of a 1.6N methyllithium solution in ether is gently addeddropwise under agitation within 15 minutes to a suspension of 4.28 g(22.5 mmol) of Cu^(I) I in 25 ml of absolute ether, and to this solutionis gradually added dropwise 2.21 g (5 mmol) of7α-(tetrahydropyran-2-yloxy)-6β-[3β-(tetrahydropyran-2-yloxy)-4-methyl-6,7-tetradehydrotrans-1-octenyl]bicyclo[3.3.0]oct-1-en-3-one(cf. DOS No. 3,142,733) in 20 ml of ether at -25° during 15 minutes.After another hour of agitation at -25° to -30° , the mixture is gentlycombined with 100 ml of NH₄ Cl solution and extracted with ether. Afterwashing with saturated sodium chloride solution, drying, andevaporation, 2.37 g of a crude product is obtained which ischromatographed on a column of 120 g of silica gel. Elution withhexane-ether (7:3 ) yielded 1.54 g (67%) of the above-mentioned product.

EXAMPLE 4 3-Oxa-9β-methyl-16-methyl-18,19-tetradehydrocarbacyclin

The 5-ring ketone described in Example 3 is reacted, according to EP No.55208, with the methyl ester of dimethoxyphosphonoacetic acid in thepresence of potassium tert-butylate, then reduced with lithium aluminumhydride, and the E-configured alkyl alcohol is finally reacted with2-chloro- or 2-bromoacetic acid salts or esters in the presence of baseswith subsequent cleavage of the tetrahydropyranyl blocking group to3-oxa-9β-methyl-16-methyl-18,19-tetrahydrocarbacyclin.

EXAMPLE 51-(2-Trimethylsilylethynyl)-7α-(tetrahydropyran-2-yloxy)-6β-[3 -tetrahydropyran-2-yloxy)-4-methyl-6,7-tetradehydrotrans-1-octenyl]bicyclo[3.3.0]octanone

At -35°, 0.33 ml (2.34 mmol) of trimethylsilylacetylene in 5 ml oftoluene is combined with 2.34 ml of 1-molar butyllithium solution inhexane and agitated for 15 minutes at -35°. Then, 2.34 ml of 1-molardiethylaluminum chloride solution in hexane is added thereto and themixture is stirred for 2 hours at 0°.

In parallel thereto, 56 mg (0.22 mmol) of sublimed nickelacetylacetonate in 3 ml of toluene is combined at -15° with 0.17 ml(0.21 mmol) of a 1.2-molar DIBAL-H solution in toluene. The black nickelsolution is then added at -15° to the above solution of1-trimethylsilyl-2-diethylaluminum acetylene.

To this solution is added, at -10°, 440 mg (1 mmol) of7α-(tetrahydropyran-2-yloxy)-6β-3α-(tetrahydropyran-2-yloxy)-4-methyl-6,7-tetradehydrotrans-1-octenyl)bicyclo[3.3.0]octen-1-en-3-oneand the mixture is stirred for 90 minutes at -b 10° whereafter it isdiluted with ether and extracted by shaking with NaH₂ PO₄ solution.After washing the organic phase with saturated NaCl solution, themixture is dried (Na₂ SO₄) and evaporated, thus obtaining 610 mg of acrude product. Chromatography with hexane-ether on silica gel yields 307mg (57%) of pure product.

EXAMPLE 6 3-Oxa-9-ethynyl-16-methyl-18,19-tetradehydrocarbacyclin

After reaction of the 5-ring ketone obtained in Example 5 with themethyl ester of dimethoxyphosphonoacetic acid, lithium aluminum hydridereduction, as well as separation of the E-, Z-isomers, the E-isomer ismade to react, as described, with 2-haloacetic acid salts or esters (cf.EP No. 55208) in the presence of bases. Subsequent splitting off of theTHP groups with acetic acid-H₂ O in THF, as well as removal of thetrimethylsilyl blocking group from acetylene in the 9-position withAgNO₃ /KCN yield the desired free carbacyclin.

We claim:
 1. A carbacyclin of the formula ##STR22## wherein n is 1 or3;R₁ is the residue ##STR23## the residue ##STR24## --COCH₃ ; theresidue --COOR₂ wherein R₂ is hydrogen; alkyl of 1-10 carbon atomsoptionally substituted by halogen, phenyl, C₁ -C₄ -alkoxy or C₁ -C₄-dialkylamino; C₄ -10-cycloalkyl; C₆ -10-aryl optionally substituted by1-3 halogen atoms, a phenyl group, 1-3 alkyl groups of 1-4 carbon atomseach or a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy,or alkoxy group of 1-4 carbon atoms; or a 5- or 6-membered heterocyclicring containing at least one O, N or S atom; or the residue CONHR₃ withR₃ meaning hydrogen or an alkanoyl or alkanesulfonyl residue each of1-10 carbon atoms;R₉ is --C.tbd.C--(CH₂)_(m) --R₆ ; m is 1-8; R₆ is OHor amino; X is an oxygen atom; Y is hydrogen or fluorine; A is a --CH₂CH₂ --, trans--CH═CH-- or --C.tbd.C--group; W is hydroxymethylene or##STR25## wherein the OH group and be in the α- or β-position; D is thegroup ##STR26## a straight-chain, saturated alkylene group of 1-5 carbonatoms, a branched saturated or straight-chain or branched unsaturatedalkylene group of 2-5 carbon atoms which latter can be optionallysubstituted by fluorine atoms; o is 1, 2 or 3; E is a direct bond, a--C.tbd.C--group, or a --CH═CR₇ --group wherein R₇ is a hydrogen atom,an alkyl group of 1-5 carbon atoms, or halogen; R₄ is an alkyl group of1-10 carbon atoms, a cycloalkyl group of 3-10 carbon atoms, or an arylgroup of 6-10 carbon atoms optionally substituted by 1-3 halogen atoms aphenyl group, 1-3 alkyl groups of 1-4 carbon atoms each, or achloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy, or alkoxygroup of 1-4 carbon atoms, or a heterocyclic group as defined for R₂ ;and R₅ is hydroxy or,when R₂ is hydrogen, a physiologically compatiblesalt thereof with a base.
 2. A compound of claim 1 whereinR₁ is COOR₂ R₂is H or C₁₋₄ -alkyl Y is H A is trans--CH═CH-- or --C.tbd.C-- D is astraight-chain saturated alkylene of 1-5 C-atoms or branched saturatedalkylene of 2-5 C-atoms E is --C.tbd.C-- and R₄ is alkyl of 1-4 C-atoms.3. 5-(E)-7-hydroxy-6-[(E)-3-hydroxy-4-methyl-oct-1-en-6-inyl]-9-[6-amino-hexyl]-bicyclo[3.3.0]octan-3-yliden-pentanic acid.
 4. 5-(E)-7-(tetrahydropyran-2-yl-oxy)-6-[(E)-4-methyl-3-(tetrahydropyran-2-yl-oxy)-oct-1-en-6-inyl]-9-[5-hydroxypentyl]-bicyclo-[3.3.0]-octan-3-yliden-pentanic acid.
 5. A pharmaceutical composition comprising an amount ofa compound of claim 1 effective to inhibit thrombocyte aggregation and apharmaceutically effective carrier.
 6. A method of inhibitingthrombocyte aggregation in a patient comprising administering to thepatient an effective amount of a compound of claim 1.